The present invention relates to novel solid forms (NSF) of fluoroquinolones, particularly to complex crystals, which have a consistent quality and improved physicochemical properties such as chemical and physical stability and higher dissolution rate.
The present invention describes co-crystals obtained from a fluoroquinolone salt and a neutral co-former, where both are solid at room temperature. For the present case we designate them as “complex co-crystals”, which have improved physicochemical properties, such as increased solubility, dissolution rate, enhanced flow properties and stability.
For the present invention, the NSF are also called co-crystals, obtained by technical experimentation. The co-crystals are chemical entities with different physicochemical properties as compared to the salts or polymorphs of the active agent on which they are based on, because of the nature of intermolecular interactions between the molecule of matter and a second solid constituent, the latter hereinafter designated as coformer.
A co-crystal is a multicomponent crystal, in which the starting components are solid under ambient conditions and in their pure form, and in which two or more components of the co-crystal form aggregates that are characterized by being bound together by interactions—such as Van der Waals forces, π-stacking, hydrogen bonding or electrostatic interactions, but without forming covalent bonds. By employing crystal engineering techniques a new substance can be obtained with modified physicochemical properties that differ from the existing polymorphs, salts, hydrates and/or solvates. The exploration adjustable parameters are better, so the physical properties of the active principle with clinical relevance can be optimized.
The pharmaceutical co-crystals are co-crystals containing at least one therapeutic molecule and a pharmaceutically acceptable co-former. In these substances, such components coexist in a well-defined stoichiometric ratio between the active ingredient and the co-former. Co-crystals in solid form tend to be more stable than the existing solvates or hydrates.
Fluoroquinolones are a group of synthetic antimicrobial agents. Structurally, they consist of a heterocyclic derivative of 4-quinolone with a fluorine atom attached to C6, as shown in Scheme I, and several substituent groups R1, R2, R3 and R4 that may be, among others, hydrogen, alkyl chains, alkoxy groups, amino, cyclopropoxy and/or heteroaromatic rings such as piperazine, cinnoline and piridopiridine at position 7 (R2).
R1 may be H, an alkyl chain or a carboxyl;R2 may be a heterocyclic amine such as pyridine, piperazine, piperidine, pirrolpiridine, pirrolpiperazine, cinnoline, morpholine, pyrrole, pyrrolidone;R3 may be an H, an alkyl chain or an alkoxy;R4 may be an H, an alkyl chain, carboxyl, cyclo propyl, indole ethanol, an alkyl chain or a linear carboxyl or attached to an alkoxy, which may or may not form a ring with R3.
The most representative fluoroquinolones are: ofloxacin, levofloxacin (S(−)enantiomer ofloxacin), enoxacin and pefloxacin, lomefloxacin, norfloxacin, ciprofloxacin, grepafloxacin (ciprofloxacin analog), sparfloxacin, tosufloxacino, gatifloxacin, trovafloxacin, clinafloxacin, sitafloxacin, moxifloxacin and gemifloxacin. The present invention develops a method of obtaining co-crystals or other solid forms starting from the salts of some of these fluoroquinolones, such as moxifloxacin, levofloxacin or ciprofloxacin.
Moxifloxacin is a fourth-generation antibiotic of the fluoroquinolone group. Its structural formula is shown in Scheme II.

In commercial pharmaceutical preparations moxifloxacin is in the form of hydrochloride salt, which is water soluble, has an absolute bioavailability of 86 to 92%, has a plasmatic protein binding of from 30% to 50%, has a half-life between 11.5 and 15.6 hours (single dose) and its excretion is via the liver [Zhanel G G et al. “A critical review of the fluoroquinolones”, Drugs, 62 (1), p. 13-59 (2002)]. This fluoroquinolone is active against gram-positive and gram-negative bacteria. It is administered orally or parenterally in a single dose of 400 mg once daily and has a good pharmacokinetic profile. Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as the unchanged drug (˜20% in urine and ˜25% in feces) [Rodvold K A et al. “Pharmacokinetics and pharmacodynamics of fluoroquinolones”, Pharmacotherapy, 21 (10 Pt 2), pp. 233S-252S (2001)].
Levofloxacin is a broad spectrum antibiotic which consists of the S(−) isomer of ofloxacin (Scheme III). Levofloxacin hemihydrate is used in commercial pharmaceutical compositions. It has a bioavailability of 99%, it has a plasmatic protein binding of from 24% to 38%, it has a half-life between 6 and 8 hours (single dose), it is administered at a dose of from 250 mg to 500 mg once or twice a day and is excreted via urine. [Pharmaceutical Press. Martindale: The complete Drug Reference. Levofloxacin. 2011. Accessed http://www.medicinescomplete.com. Apr. 12, 2011].

Ciprofloxacin is a broad spectrum antibiotic that belongs to the family of antibiotics called fluoroquinolones, and its chemical formula is shown in Scheme IV. It is effective against gram-positive and gram-negative bacteria, it functions by inhibiting the DNA gyrase, a type II topoisomerase which is an enzyme required to separate the replicated DNA, inhibiting cellular division. Pharmaceutical compositions employ ciprofloxacin hydrochloride, a salt which is soluble in water and alcohol. In a 2.5% water solution it has a pH of from 3.5 to 4.5. It must be protected from light. Ciprofloxacin is rapidly and well absorbed from the gastrointestinal tract. The oral bioavailability is from 70% to 80%, the absorption of ciprofloxacin tablets may be delayed by the presence of food, but not substantially affected as a whole; it has a plasma protein binding of from 20% to 40%, it has a half-life of from 3 to 5 hours (single dose) and is excreted through kidney route. [Pharmaceutical Press. Martindale: The complete Drug Reference. Ciprofloxacin. 2011. Accessed http://www.medicinescomplete.com. Apr. 12, 2011].
Adverse Effects
In general, fluoroquinolones are well tolerated, however, the most common side effects are: effects on the articular growth, erosion of the cartilage in growth, especially in weight-bearing joints. For this reason fluoroquinolones should not be administered to children and adolescents under 18 years old. The most serious adverse effect is particularly of cardiologic type as the duration of the QT interval of the electrocardiogram might be affected. If this interval is abnormally prolonged, may generate arrhythmias.
Interactions with Other Medicaments
Fluoroquinolones enhance the effect of anticoagulants and may enhance the hypoglycemic effect of sulfonylureas. Furthermore, aluminum salts (including sucralfate), magnesium, calcium, iron and zinc, significantly reduce the bioavailability of fluoroquinolones by non-absorbable chelators formation.